Composition comprising arylaminooxazoline and antichloligeneric agent

ABSTRACT

17. A composition comprising one part by weight of an arylaminooxazoline and from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said arylaminooxazoline being selected from the group consisting of those of the following formulas and pharmaceutically acceptable acid addition salts thereof: WHERE IN EACH OF FORMULAS (1) THROUGH (6) R, R1, R2 and R3 are each separately selected from the group consisting of hydrogen and alkyl of 1 through 4 carbons with the total number of carbons in these four substitutents being 8; where in each of formulas (1) through (5), 1 through 3 hydrogen atoms of the moiety selected from the group consisting of naphthyl, partially reduced naphthyl and indanyl can be replaced with a member selected from the group consisting of halogen, alkyl of 1 through 4 carbons, alkoxy of 1 through 4 carbons, alkylthio of 1 through 4 carbons, trifluoromethyl and trifluoromethoxy; and where in formula (6) A is selected from the group consisting of hydrogen, alkyl of 1 through 4 carbons, alkoxy of 1 through 4 carbons and halogen; B is selected from the group consisting of alkyl of 1 through 4 carbons, alkoxy of 1 through 4 carbons and halogen; and C is selected from the group consisting of hydrogen, alkyl of 1 through 4 carbons, alkoxy of 1 through 4 carbons halogen, alkylthio of 1 through 4 carbons, alkoxyalkyl wherein the alkoxy portion has 1 through 2 carbons and the alkyl portion has 1 through 2 carbons, alkylamino of 1 through 2 carbons, dialkylamino where each alkyl group has 1 through 2 carbons, trifluoromethyl and trifluoromethoxy.

United States Patent Culik et al.

[451 July 25, 1972 Square, Pa. 19348; Jurg A. Schneider, 520 Rothbury Road, Wilmington, Del. 19808 [73] Assignee: E. I. du Pont de Nemours and Company,

Wilmington, Del.

[22] Filed: Feb. 28, 1964 [21] Appl. No.: 348,291

[52] U5. Cl ..424/265, 424/247, 424/251,

424/263, 424/267, 424/272, 260/307 D, 260/307 F [51] Int. Cl. .,A61k 27/00 [58] Field of Search ..260/553, 307; 167/65; 424/247,

[56] References Cited UNITED STATES PATENTS 2,027,031 1/1936 Englelmann ..260/44 2,870,160 -l/1959 Bloom ..260/307 Primary Examiner-Leland A. Sebastian A1mrr|eyl-1erbert Wv Larson EXEMPLARY CLAIM 17. A composition comprising one part by weight of an arylaminooxazoline and from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said arylaminooxazoline being selected from the group consisting of those of the following formulas and pharmaceutically acceptable acid addition salts thereof:

wherein each of formulas 1 through (6) R, R, R and R are each separately selected from the group consisting of hydrogen and alkyl of 1 through 4 carbons with the total number of carbons in these four substitutents being 8; where in each of formulas (1) through (5), 1 through 3 hydrogen atoms of the moiety selected from the group consisting of naphthyl, partially reduced naphthyl and indanyl can be replaced with a member selected from the group consistingof halogen, alkyl of 1 through 4 carbons, alkoxy of 1 through 4 carbons, alkylthio of 1 through 4 carbons, trifluoromethyl and trifluoromethoxy; and where in formula (6) A is selected from the group consisting of hydrogen, alkyl of 1 through 4 carbons, alkoxy of 1 through 4 carbons and halogen; B is selected from the group consisting of alkyl of 1 through 4 carbons, alkoxy of 1 through 4 carbons and halogen; and C is selected from the group consisting of hydrogen, alkyl of 1 through 4 carbons, alkoxy of 1 through 4 carbons halogen, alkylthio of 1 through 4 carbons, alkoxyalkyl wherein the alkoxy portion has 1 through 2 carbons and the alkyl portion has 1 through 2 carbons, alkylamino of 1 through 2 carbons, dialkylamino where each alkyl group has 1 through 2 carbons, trifluoromethyl and trifluoromethoxy.

32 Claims, No Drawings COMPOSITION COMPRISING ARYLAMINOOXAZOLINE AND ANTICHLOLIGENERIC AGENT This invention relates to pharmaceutical compositions useful for both human and veterinary applications. More particularly, this invention relates to synergistic utilization of one or more centrally acting anticholinergic substances and one or more of a class of central nervous system depressants.

The disclosure herein should not be taken as a recommendation to use the disclosed invention in any way without full compliance with US. Food and Drug laws and other laws and governmental regulations which may be applicable.

According to the present invention, an amazing synergism has been noted between a centrally acting anticholinergic and compounds in a class generically identified as 2-arylamino-2- oxazolines. While the oxazolines themselves have activity, some to a remarkable extent, as regulators and in particular depressants of the central nervous system, we have now discovered that, when used with a centrally acting anticholinergic, the synergistic combination according to this invention effects a profound action, producing a striking depression of central nervous system control of skeletal muscle as well as a striking loss of response to painful stimuli. This effect resembles a deep surgical anesthesia, producing unconsciousness in the recipient in a very short time.

Centrally acting anticholinergics are a well-recognized class of pharmacologically active substances. As is well known and understood by pharmacologists, these anticholinergics can be naturally occurring or synthetic and are those substances which act to inhibit and have a highly selective blocking action on effector organs innervated by postganglionic cholinergic nerves. As is known to personS skilled in this art, anticholinergic agents containing a quaternary nitrogen moiety are of course not centrally acting.

Perhaps the best known centrally acting anticholinergics are the natural occurring alkaloids of the belladonna plants. The two most important of these alkaloids are atropine (dlhyoscyamine) and scopolamine (l-hyoscine) and these two materials are the preferred synergists according to the present invention because of their significantly outstanding synergizing action with the 2-arylamino-2-oxazolines. Also of special importance because of outstanding activity are the centrally acting anticholinergic glycolat es.

However, the use of all centrally acting anticholinergic substances is intended to be embraced within the concept of the present invention. Illustrative of such anticholinergics are the following:

Adephenine (Registered trademark), also identified as Trasentine (Registered trademark and 2- diethylaminoethyl diphenylacetate benactyzine, also identified as beta-diethylaminoethyl benzilate benztropine, also identified as 3-diphenylmethyoxytropane caramiphen, also identified as lphenylcyclopentane-carboxylic acid, diethylaminoethyl ester cyclopentolate, also identified a l-hydroxy-alpha-phenylcyclopentaneacetic acid, Z-dimethylamino-ethyl ester cycrimine, also identified a]phacyclopentyl-alpha-phenyll-piperidinepropanol Ditran, also identified as N-ethyl-3-piperidyl phenyl cyclopentyl glycolate ethopropazine, also identified as l0-( Z-diethylaminopropyl) phenothiazine oxyphencyclimine, also identified as l-methyl-l,4,5,6-

tetrahydro-Z-pyrimidylmethyl alpha-cyclohexyl-alphaphenylglycolate piperidolate, also identified as N-ethyl-3-piperidyl diphenylacetate systral, also identified as chlorphenoxamine and betadimethylaminoethyl (p-chloro-alpha-methylbenzhydryl)ether tricyclamol, also identified as procyclidine and alphacyclohexyl-alpha-phenyll-pyrrolidine-propanol trihexphidyl, also identified as alpha-eyclohexyl-alphaphenyll -piperidinepropanol In addition to the above-mentioned anticholinergics, other illustrative materials include homotropine, atroscine, eucatropine, syntropan (amprotropine), pavatrine, banthine (methantheline), pro-banthine (propantheline), oxypenonium (antrenyl), penthienate (monodral), diphenmethanil (prantal), mepiperphenidol (darstine), dicyclomine (bentyl), aminopentamide (centrine), dibutoline and the like.

As will be readily understood, the centrally acting anticholinergics will most often be used in the form of an acid addition salt with anacid having a pharmaceutically acceptable anion. The term pharmaceutically acceptable anion" has a definite meaning to one skilled in the art, namely, a nontoxic anion of any of the simple acids commercially used to neutralize basic medicinal agents. These acids include, for example, hydrochloric, hydrohromic, hydriodic, sulfuric, succinic, maleie, tartaric, citric, glycolic, and others. The pharmaceutical activity ofthc molecule is primarily but not necessarily exclusively a function ofthe cation,

By way of further illustration of the salts of anticholinergie agents, it can be mentioned that atropine is preferably used as the hydrobromide, hydrochloride, methylbromide, methylnitrate, salicylate, sulfate, atropine-sulfuric acid, valerate, aurichloride, platinichloride, oxalate or picrate; scopolamine as the hydrobromide, hydrochloride, aurichloride, auribromide, picrate, methylbromide, methylnitrate or aminoxide; Adephenine (Registered trademark) as the hydrochloride; benactyzine as the hydrochloride; benztropine as the methanesulfonate; caramiphen as the hydrochloride or ethanedisulfonate; cycrimine as the hydrochloride; oxyphencyclimine as the hydrochloride; systral as the hydrochloride; and trihexyphenidyl as the hydrochloride.

The second essential ingredient of the synergistic compositions of the present invention is a 2-arylamino-2-oxazoline having central nervous system depressant activity. Suitable 2- arylamino-2-oxazolines include those of the fOllowing formulas:

In each of the aboVe formulas, R, R, R and R' are the same or different and can each be hydrogen or an alkyl group of one through fOur carbons with the total number of carbons in these four substituents being a maximum of eight. In the compounds of Formulas 1) through the hydrogen atoms of the naphthyl, the partially reduced naphthyl or the indanyl groups may be replaced with substituents such as halogen, e.g., chlorine, bromine, fluorine and iodine, alkyl of one through four carbons, alkoxy of one through four carbons, alkylthio of one through four carbons, trifluoromethyl and trifluoromethoxy. Up through three such substituents can be present.

In Formula (6), A can be hydrogen, alkyl of one through four carbons, and preferably one or two carbons, alkoxy of one through four carbons, and preferably one or two carbons, or halogen including chlorine, bromine, and fluorine; B can be alkyl of one through four carbons and preferably one or two carbons, alkoxy of one through four carbons and preferably one or two carbons, or halogen including chlorine, bromine and fluorine; and C can be hydrogen, alkyl of one through four carbons and preferably one or two carbons, alkoxy of one through four carbons and preferably one or two carbons, halogen including chlorine, bromine and fluorine, alkythio of one through four and preferably one or two carbons, alkoxyalkyl wherein the alkoxy portion has one or two carbons and the alkyl portion has one or two carbons, alkylamino of one or two carbons, dialkylamino where the alkyl group can be the same or different and each has one or two carbons, trifluoromethyl or trifluoromethoxy.

Preparation As will be noted, the compounds of Formula (1) are substituted and unsubstituted 2-(1naphthylamino)-2-oxazolines.

These compounds and a method for their preparation are described in Bloom U.S. Pat. No. 2,811,529 issued Oct. 29,

The compounds of Formula (2) are substituted and unsubstituted 2( l,2,3,4-tetrahydro-lnaphthylamino)-2-oxazolines. A method for their preparation is described in bloom U.S. Pat. No. 2,870,159 issued Jan. 20, 1959.

The compounds of Formula (3) are substituted and unsubstituted 2-( l-indanylamino)-2-oxazolines. A method for their preparation is described in Bloom U.S. Pat. No. 2,870,161 is- ,sued Jan. 20, 1959.

The compounds of Formula (4) are substituted and unsubstituted 2-(5,6,7,8-tetrahydro-1naphthylamino)-2-oxa2olines. The compounds of formula (5) are substituted and unsubstituted 2-( 5 ,6,7 ,S-tetrahydrol -naphthylamino )-2-oxazolines. The compounds of Formula (5) are substituted and unsubstituted 2 -(4-indanylamino)-2-oxaz0lines. These compounds of Formula (4) and (5) have remarkably superior activity as central nervous system depressants compared with the compounds of Formulas (2) and (3). The compounds of formulas 4) and 5 are claimed and their preparation described in copending U.S. patent application Ser. No. 313,756 filed Sept. 30, 1963 now U.S. Pat. No. 3,432,600, in the name of John Harvey, Jr., and assigned to the same assignee as that of the present invention.

The compounds of Formula (6) are substituted 2-anilino2- oxazolines. They are characterized byputstanding anti-hypertensive and central nervous system depressant properties. Their pharmaceutical use is claimed and their preparatiOn described in copending U.S. patent application Ser. No. 348,290 filed Feb. 28, 1964 now abandoned, in the name of John Harvey, Jr., and assigned to the same assignee as that of the present application. In the last-mentioned Harvey application, a preferred group of compounds having unusual effectiveness is also claimed.

Generally, the compounds of Formulas l through (6) are crystalline solids, they can be readily prepared by reactiOn of 70 In the foregoing procedures, the reaction between the amine and isocyanate can conveniently be carried out in a suitable inert organic solvent including both aromatic and aliphatic hydrocarbon solvents. Halogenated, oxygenated or nitrated hydrocarbon solvents are useful. Representative solvents are benzene, chloroform carbon tetrachloride, ethylene dichloride, chlorobenzene, toluene, xylene, nitrobenzene andnitrotoluene. Temperatures in the range from 0 to 1 10C. are suitable.

Formation of the aryloxazoline is conveniently carried out by refluxing the urea in solution in a suitable solvent such as methanol, ethanol, propanol, butanol or preferably water, with elimination of hydrogen bromide, hydrogen chloride, hydrogen iodide, methanesulfonic acid, p-toluenesulfonic acid or the like. Since the oxazolines are basic in nature, the liberated acid adds to the oxazoline to form an acid addition salt. The free base is liberated from the salt using an alkaline reagent such as ammonium hydroxide, sodium hydroxide, sodium bicarbonate, calcium oxide or the like.

Useful synthesis techniques are described in Chem.

Reviews, Vol.44, pages 463-466 1949).

By reference to the reaction described above, it can be seen that in the ordinary practice of the process of the invention, the oxazolines produced will be hydrobromides, hydrochlorides, hydriodides, methanesulfonic acids or ptoluenesulfonic acids. These acids can be converted to other pharmaceutically acceptable acids by procedures well known to those skilled in the art. One highly useful method comprises contacting the acid addition salt with a basic anion exchange resin, for example, a highly basic compound such as the one available from Rohm & Haas Company under the name Amberlite IRA-400." This resin is a polyquaternary ammonium compound which is prepared by chloromethylating a highly cross-linked copolymer of styrene and divinylbenzene followed by treatment of the chloromethylated material with a tertiary amine such as trimethylamine. To prepare an acid addition salt of this invention, for example, the citrate, the resin is first contacted with an aqueous solution of citric acid whereupon an anion exchange takes place converting the quaternary halide to the citrate. The citrate resin is then contacted with an acid addition salt prepared as described above and a further anion exchange takes place converting the acid addition salt to the citrate and leaving the anion of the original salt on the resin. The citrate salt can be recovered from the el uate by a number of methods such as evaporation or solvent precipitation. This same procedure can be used to prepare nitrates, sulfates, acetates and other acid addition salts.

Illustrative of the compounds within the scope of Formula l above are the following:

2-( 3,4-dichoro-1-naphthylaminotZ-oxazoline 2-( 3-bromo-1-naphthylamino-2-oxazoline 2-(4-ethyl-1-naphthylarnino)-4,5-dimethyl-2-oxa2olin 2-( 3 ,4,5-triiodol -naphthylamino )-2-oxazoline 2-( 3,4-bismethylthiol -naphthylamino)4-butyl-2-oxazoline 2-(2,3,5-tri-sec-butoxy-1-naphthylamino)-2-oxazoline 2-( 3,4-dimethoxyl -naphthylamino)-4,5-diethyl-2-oxazoline 2-(4-tert-butylthio-1-naphthylamino)-2-oxazoline 2-( 3 ,4-diethoxyl -naphthylamino )-4,5-dimethyl-2-oxazoline 2-( 4-isopropylthiol-naphthylamino )-5-ethyl-2-oxazo1ine Illustrative of the compounds within the scope of Formula (2) above are the following: v

2-( 1,2,3 ,4'tetrahydro-3 ,4-dichlorol -naphthylamino )-2-oxazoline 2( l,2,3,4-tetrahydr-3,4,S-triiodo-l-naphthylamino)-2-oxazoline 2-( l ,2,3,4,-tetrahydro-3,4,5-trimethyll -naphthylamino)-2- oxazoline 2-( l ,2,3,4-tetrahydro-3,4-dimethoxyl -naphthylamino)- 4,5-diethyl-2-oxazoline 2-( l ,2,3 ,4-tetrahydro-4-tetrahydroisopropyll naphthylamino)-5-ethyl-2oxazoline azoline 2(5,6,7,8-tetrahydro 3,4-dimethyll -naphthylamino)-2- oxazoline 2( ,6,7,8-tetrahydrol -naphthylamino)-4-butyl-2-oxazoline 2( 5 ,6,7,8-tetrahydro-2-methyll -naphthylamino)-2'oxazoline 2( 5,6,7,8-tetrahydro-4-chlorol -naphthylamino)-2-oxazoline 2-( 5,6,7,8-tetrahydro-2,4-diiodol -naphthylamino )-2-oxazoline 2(5,6,7,8-tetrahydro-2,5-dibromo-l-naphthylamino)-4- butyl-2-oxazoline 2(5,6,7,8-tetrahydro-2,3,4-trimethylthio-l-naphthylamino)-2-oxazoline 2(5,6,7,8-tetrahydro-4-fluoro-1-naphthylamino)-4,5-

dimethyl-Z-oxazoline 2(5,6,7,8tetrahydrO-ZA-diethyI-l-naphthylamino)-2-oxazoline 2( 5 ,6,7,8-tetrahydro-2,3-dimethoxyl -naphthylamino)-4- methyl-2-oxazoline 2(5,6,7,8-tetrahydro-2,3,5-tri-sec-butoxy-l-naphthylamino)-2-oxazoline 2( 5,6,7,8tetrahydro-2,5-dimethylthiol -naphthylamino)- 4-methyl5-sec-butyl-2-oxazoline 2(5,6,7,8-tetrahydro-2,5-bisethylthio-l-naphthyl-amino)- 4,5-dimethyl-2-oxazoline 2(5,6,7,8tetrahydro-2,3-diethoxy-l-naphthylamino)-2-oxazoline 2( 5 ,6,7,8-tetrahydro-3,4-dichlorol -naphthylamino)-2-oxazoline 2(5,6,7,8-tetrahydro-3-bromo-l-naphthylamino)-4- methyl-2-oxazoline 2-(5,6,7,8-tetrahydro-3,4,5-triiodo-l-naphthylamino)-4,5-

dimethyl-Z-oxazoline 2( 5 ,6,7,8-tetrahydro-4-isopropyl-1-naphthylamino)-2-oxazoline 2( 5,6,7,8-tetrahydro-4-trifluoromethyll -naphthylamino)- 2-oxazoline 2(5,6,7,8-tetrahydro-4-trifluoromethoxy-lnaphthylamino)-2oxazoline Illustrative of the compounds within the scope of Formula (5) above are the following:

2(4-indanylamino)-2-oxazOline 2(2-chloro-4-indanylamino)-2-oxazoline 2-( 2,5-diiodo-4-indanylamino)-2-oxazoline 2( 3,5-bis-propylthio-4-indanylamino )v-2-oxazoline 2(2-methyl-4-indanylamino)-2-oxazoline Illustrative of the compounds within the scope of Formula (6) are the following:

2( Z-tol uidino )-2-oxazoline 2(2,3-dimethylanilino)-2-oxazoline 2( 3-chloro-2-methylanilino)-2-oxazoline 2(Z-ethylanilino)-2-oxazoline 2( 3,4-dimethylanilino)-2-oxazoline 2( 3-isopropylanilino)-2-oxazoline 2( 2,3,4-trichloroanilino)-2-oxazoline 2(4-methoxy-Z-methylanilino)-2-oxazoline 5-methyl-2-( 2,3-dimethylanilino)-2-oxazoline 4-ethyl-2-( 2,3-dimethylanilino)-2-oxazoline 4,4-dimethyl-2-( 2-methyl-3-chloroanilino)-2-oxazoline 5-butyl-2-( 2-methylanilino)-2-oxazoline 2( Z-dimethylaminoanilino)-2-oxazoline 2( 3-methylthioanilino)-2-oxazoline 2( 2-trifluoromethylanilino)-2-oxazoline 2-( Z-trifluoromethoxy-3-methylanilino )-2-oxazoline 2( 2,4,5-trimethylanilino)-2-oxazoline 4-methyl-2-(2-methyl-5-isopropylanilino)-2-oxazoline 2(2,5-dimethoxyanilino)-2-oxazoline 5-methyl-2-( 2,4-dimethoxy-S-chloroanilino)-2-oxazoline 2(2-fluoroanilino)-2-oxazoline 2(2-bromo-4-methylanilino)-2-oxazoline 2(2,5-diethoxyanilino)-2-oxazoline 2( 3-chloro-4-methylanilino)-2oxazollne 2(2,6-diethylanilino)-2-oxazolinc 2(4-chloro-2-trifluoromethylanilino)-2-oxazoline 2( 3-chloro-4-fluoroanilino )-2-oxazoline 2(4-fluoro-2-methylanilino)-2-oxazoline In the practice of the present invention it should be fully appreciated that administration of the anticholinergic and the arylaminooxazoline for the intended profound depressant effect will be more or less concurrent, i.e., united in action, and not necessarily simultaneously, i.e., in the same pharmaceutical formulation or dosage unit. Thus, it will be understood that the synergistic benefits of the present invention will be readily obtainable even though either one or the other of the two essential materials may be administered somewhat prior to or subsequent to the administration of the other. For example, for gradual inducement of profound central nervous system depression with apparent unconsciousness in a patient, it may under some circumstances be desirable to administer first the arylaminooxazoline, perhaps orally, followed within say 30 minutes or an hour by administration, perhaps by injection, of the synergistic amount of the anticholinergic agent.

Of course the precise length of time which can elapse between administration of the anticholinergic and the arylaminooxazoline, or vice versa, to still obtain the synergistic co-action of the compounds has not been determined for each combination of the two different materials possible according to this invention. The precise time lapse will depend on the amount of each administered, the condition of the recipient, the absorption characteristics of each material, the dosage form or method, the nature of the effect desired, etc., as will be determined by the attendant physician or veterinarian. Generally speaking, it is believed that provided the dosages of each are sufiicient, the synergistic action is obtainable if the two components are administered within, say, 2 or 3 hours of each other.

The amount of each of the two essential materials to be administered will of course also depend upon the variables just mentioned but, in general, the arylamino-oxazoline will be administered in the range of about 0.] to 500 milligrams per day. For the synergistic effect, for each part by weight of arylaminooxazoline used, there will usually be used from about 0.5 to about 30 parts by weight of anticholinergic agent, and preferably about 0.5 to about 5 parts by weight of the latter. The absolute potency of each of the ingredients will of course be the prime determining factors.

As mentioned above, in general, the physician or veterinarian will, of course, determine the dosage of each and the total dosage which will be most suitable for a particular application, and as might be expected, it will vary with the age, weight and general health of the patient under treatment and with various other factors which will be determined by the physician or veterinarian in attendance. When they are administered orally a larger quantity will be required to produce the same effect as a smaller quantity given parenterally. Parenteral administration of from 0.1 mg. to 250 mg. of each active agent should be suitable to obtain some effect. Administration can also be by vapor or spray through the mouth or nasal passages.

In animal tests to date no synergism of cardiovascular actions has thus far been noted. Furthermore, based on tests to date, it is believed that the surprising synergism in inducement of profound central nervous system depression obtained according to the present invention is achieved without at the same time substantially altering the normally expected effect of centrally acting anticholinergic agents on the heart rate.

In the practice of this invention, the active pharmaceutical agents may be administered alone but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets or capsules containing such excipients as starch, milk sugar, certain types of clay, etc. They may be administered orally in the form of elixirs or oral suspensions which may contain coloring and flavoring agents. They may be injected parenterally and for this use may be prepared in the form of sterile aqueous solutions containing other solutes such as saline or glucose in sufficiefit quantity to make the solution isotonic. For intramuscular administration compositions of the compounds of this invention may be prepared in an oil base such as peanut or sesame oil.

Compositions useful in the practice of the present invention may take a variety of forms. Various diluents may be employed and the percentage of active ingredients may be varied. It is necessary that the active ingredient or ingredients form a proportion of the composition such that a suitable dosage form will be obtained. Obviously several dosage unit forms can be administered at about the same time. Although compositions with less than 0.005 percent by weight of either active ingredient are Suitable, it is preferred to use compositions containing not less than 0.005 percent of either active agent because otherwise the amount of carrier becomes excessively large. Activity normally increases with the concentration of the active agent. The percentage by weight of single or combined active agents can be l0, 50, 75, 95 percent or even higher. Dosage unit forms may be prepared with a minor proportion of a carrier and a major proportion of active materials and vice versa.

The following examples are given solely for the purpose of illustration and are not to be construed as limitations of this invention, many variations of which are possible without departin g from the spirit or scope thereof.

EXAMPLE 1 A large number of unit capsules are prepared for oral administration by mixing the following ingredients:

Parts by Weight 2-( 5,6,7,8-tetrahydro-l-naphthylamino)-2oxazoline 650 scopolamine hydrobromide L300 lactose U.S.P. 8,000 Dry pyrogenic silica SiO with 50 particle size of 0.0 l 5 microns, surface area of 200 m /gm, and bulk density of 2.2 lbs/cu.ft.

(Cabosil, Cabot Corp.)

After mixing, the mixture is screed through a 40 mesh screen and encapsulated in No. 3 two-piece hard gelatin capsules.

EXAMPLE 2 The active ingredients of Example 1 parts by weight) is dispersed in 100 parts by volume of corn oil and encapsulated in standard soft gelatin capsules.

EXAMPLE 3 100 milligrams of starch, and forming the mixture into tablets 7 by a conventional tableting machine. Slow release pills and tablets can also be used.

EXAMPLE 4 A parenteral composition suitable for administration by injection is prepared by dissolving 5 percent by weight of the active ingredients of Example 1 in 95 percent by volume of physiological saline and sterilizing the resultant solution by filtration. A buffer can be used if desired.

EXAMPLE 5 2-( 5 ,6,7,8-tetrahydrolnaphthylamino )-2-oxa2oline (O. 2 parts by weight) is dissolved at a concentration of 2 milligrams per milliliter in a mixture of 25 parts by weight of polyethylene glycol (Carbowax" 400) and parts by weight of physiological saline. The resulting solution is then combined with an equal volume of a solution of 4 milligrams of atropine sulfate dissolved in l milliliter of physiological saline. The combined solution is injected into the cephalic vein of a 2-year old beagle dog so that a total of0.l milligram ofthe oxazoline and 0.2 milligram of the atropine sulfate, per kilogram of body weight of the dog, is administered. In about 15 minutes the animal becomes depressed and passes into a state of deep central nervous system depression in which the animal does not respond to painful stimuli. This state lasts for about 1 to 2 hours following which the animal recovers normal functions with no deleterious after-effects.

EXAMPLE 6 A 1-year old female dog is given an intravenous injection of atropine sulfate dissolved in 0.4 percent by weight concentration in physiological saline. The injection is sufficient to introduce 0.2 milligram of the atropine sulfate per kilogram of body weight of the dog. The injection of atropine sulfate is followed l0 minutes later by intravenous injection of 2-(5,6,7,8- tetrahydro-l-naphthylamino)-2-oxazoline, dissolved in 0.2 percent by weight concentration in polyethylene glycol (25 parts) and physiological saline (75 parts), in amount sufficient to introduce 0.1 milligram of the oxazoline per kilogram of body weight. In about 15 minutes the animal becomes depressed and passes into a state of deep central nervous system depression in which the animal does not respond to painful stimuli. This state lasts for about 1 to 2 hours following which the animal recovers normal functions with no deleterious after-effects.

EXAMPLE 7 2-(2,3-dimethylanilino)-2-oxazoline (3 parts by weight) is dissolved in 1,000 parts by weight of a mixture of 25 pans by weight of polyethylene glycol (Carbowax 400) and 75 parts by weight of physiological saline. The resulting solution is injected intravenously into a 2-year old male dog in an amount to introduce 0.132 milligram of oxazoline per kilogram of body weight of the dog. This injection is followed in 10 minutes by intravenous administration of a normal saline solution of atropine sulfate, sufficient to introduce 0.5 milligram of atropine sulfate per kilogram of body weight of the dog. In about 15 minutes the animal becomes depressed and passes into a state of deep central nervous system depression in which the animal does not respond to painful stimuli. This state lasts for about 1 to 2 hours following which the animal recovers normal functions with no deleterious after-effects.

mide is used in place of the atropine sulfate, with similar results.

EXAMPLE 9 3) T: if Example 6 is repeated, except that in place of the atropine sulfate there is used an amount of phenyl cyclopentylglycolic '-NII acid, N-ethylpiperidinol ester, sufficient to introduce 0.2 milligram of the ester per kilogram of body weight of the dog, with a similar results. R

4 R EXAMPLE 0 Example 5 is repeated, except that in place of the atropine l0 there is used an amount of benzilic acid, betadiethylaminoethyl ester, sufficient to introduce 0.1 milligram N I of the ester per kilogram of body weight of the dog, with similar results. (5) R (g EXAMPLE 11 Rhesus monkeys are exposed for 5 minutes in a dynamic l chamber to an atmosphere containing 400 micrograms per liter of 2-(5,6,7,8-tetrahydro-l-naphthylamino)-2-oxazoline 2O Ra and 800 micrograms per liter of scopolarnine aspirated into and the chamber in the form of an aerosol. Within 3 to 5 minutes (6) R the animals become prostrate, severely depressed and ap- A parently unconscious for a period of about 1 hour. NH i o EXAMPLES 12 26 B l The procedures of Examples 5 and 6 are repeated except a that the following listed anticholinergic agents and where in each of Formulas l through (6 R, R, R and R arylaminooxazolines are substituted in like amount by weight are each separately selected from the group consisting of for those of Examples 5 and 6 respectively. They are ad- 30 hydrogen and alkyl of one through four carbons with the ministered in like manner and provide like results. total number of carbons in these four substituents being Amount Amount (mg/kg.) 2-oxazoline (mg/kg.) Anticholincrgic Example:

1 0. 25 2-(1-naphtl1ylamin0)- 0. 500 Atropine sulfate.

0.2 2-(4-metlioxy-1-naplrthylumino)- 0.400 Scopolamino. lrydrobromidv. 0.2 do 5.00 Bonzetyzine. 0.2 2-(2-rncthyl-l-naphthylamin0) 7. 0.400 Scopolumine hydrobromide. 1.0 2-(4-methyl-1-naphtliylmnino)- 1.00 Atropine sulfate. 0.1 2-(5,6,7,8;tctrahydro-1-napl1thyl- 10.00 Trasentine.

{11111110 0.1 2-(a-mcthyl-5,6,7,8-tetrahydro-l-naph- 0.500 Benztropine.

thylan1ino)-v 0. 5 2-(4-n1ethoxy-5,6,7,8-tetrahydro-1- 1. 00 Ditran.

naphthylamino)-. 0.1 2-(1,2,3,itetrahydro-l-naphthyl- 25.00 Caramiphen.

amino, 0,25 2 (2-rnethylanilino)- 0.500 Cyclopentolate.

, 5. 00 Cycrimine hydrochloride.

50. 0 Ethopropazine. 50.0 Iiparidolate. 20. 0 ()xyphencyclimino. 5. U0 'lricycluniol.

The invention claimed is: 5 8; where in each of Formulas (1) through (5), one 1. The method comprising administering toawarm-blooded through three hydrogen atoms of the moiety selected animal two essential substances within 3 hours of each other, from the group consisting of naphthyl, partially reduced the first essential substance being a centrally acting annaphthyl and indanyl can be replaced with a member ticholinergic agent and the second essential substance being selected from the group consisting of halogen, alkyl of selected from the group consisting of a 2-arylamino-2-oxone through four carbons, alkoxy ofone through four carazoline and pharmaceutically acceptable acid addition salts on a y h of one through four carbons, thereof, there being used from about 0.5 to 30 parts by weight trifluoromethyl and trifluoromethoxy; and of said anticholinergic agent for each part by weight of said Where i Formula A is Selected f m h gr up nsis second essential substance, and said 2-arylamino2-oxazoline ing of hydrogen. alkyl of On h gh f Carbon-S, alkoxbeing a compound selected from the group consisting of y of one through four carbons and halogen;

B is selected from the group consisting of alkyl of one (1) R through four carbons, alkoxy of one through four carbons g I and halogen; and R C is selected from the group consisting of hydrogen, alkyl of NHO one through four carbons, alkoxy of one through four carbons, halogen, alkylthio of one through four carbons, al-

1 koxyalkyl wherein the alkoxy portion has one through two carbons and the alkyl portion has one through two (2) R carbons, alkylamino of one through two carbons, dial- & kylamino where each alkyl group has one through two carbons, trifluoromethyl and trifluoromethoxy. i 2. The method according to claim 1 where said centrally -11: acting anticholinergic is a glycolate.

3. The method comprising administering to a warm-blooded animal, within an hour of each other, a compound selected 'from the group consisting of 2-(1 -naphthylamino)-2-oxazoline and pharmaceutically acceptable acid addition salts of pound, from about 0.5 to 30 parts by weight of a centrally act-' ing anticholinergic agent, said oxazoline having the formula (ME-R1 sisting of hydrogen and alkyl of one through four carbons with the total number of carbons in each of these four substituents being eight; and where one through three of the hydrogen selected from the group consisting of halogen, alkyl of one through four carbons, alkoxy of one through four carbons, alkylthio of one through four carbons, trifluoromethyl and 4. The method comprising administering to a warm-blooded animal, within a hour of each other, a compound selected from the group consisting of a 2-( l,2,3,4-tetrahydrol acid addition salts of said oxazoline and, for each one part by weight of said compound, from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said oxazoline havsaid oxazolin'e and, for each one part by weight of said comwhere R, R, R and R are each selected from the group conatoms in the naphthyl group can be replaced with a member trifluoromethoxy.

naphthylamino)-2-oxazoline and pharmaceutically acceptable ing the formula where R, R, R arid R are each selected from the group consisting of hydrogen and alkyl of one through four carbons with the total number of carbons in each of these four substituents being eight; and where one through three of the hydrogen atoms in the partially reduced naphthyl group can be replaced with a member selected from the group consisting of halogen, alkyl of one through four carbons, alkoxy of one through four carbons, alkylthio of one through four carbons, trifluoromethyl andtriiluoromethoxy.

5. The methodcornpr'ising administering to a warm-blooded animal, withii'ihhhour of each other, a compound selected from the group consisting of a 2-( l-indanyl)-2-oxazoline and pharmaceutically acceptable acid addition salts of said oxazoline and, for each one part by weight of said compound, from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said oxazoline having the formula where R, R, R, and R are each selected from the group consisting of hydrogen and alkyl of one through four carbons with the total number of carbons in each of these four substituents being eight; and where one through three of the hydrogen atoms in the indanyl group can be replaced with a member selected from the group consisting of halogen, alkyl of one through four carbons, alkoxy of one through four carbons, alkylthio of one through four carbons, trifluoromethyl and trifluoromethoxy.

6. The method comprising administering to a warm-blooded animal, within an hour of each other, a compound selected from the group consisting of a 2-(5,6,7,8-tetrahydrol naphthylamino)-2-oxazoline and pharmaceutically acceptable acid addition salts of said oxazoline and, for each one part by weight ofsaid compound, from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said oxazoline hav ing the formula:

where R, R, R and R are each selected from the group consisting of hydrogen and alkyl of one through four carbons with the total number of carbons in each of these four substituents being eight; and where one through three of the hydrogen atoms in the partially reduced naphthyl group can be replaced consisting of halogen, alkyl of one through four carbons, al koxy of one through four carbons, alkylthio of one through four carbons, trifluoromethyl and trifluoromethoxy.

7. The method comprising administering to a warm-blooded animal, within an hour of each other, a compound selected from the group consisting of a 2-(4-indanylamino)-2-oxazoline and pharmaceutically acceptable acid addition salts of said oxazoline and, for each one part by weight of said com' pound, from about 0.5 to 30 parts by weight ofa centrally acting anticholinergic agent, said oxazoline having the formula Ra where R, R, R and R are each selected from the group consisting of hydrogen and alkyl of one through four carbons with the total number of carbons in each of these four substituents being eight; and where one through three of the hydrogen atoms in the indanyl group can be replaced with a member selected from the group consisting of halogen, alkyl of one through four carbons, alkoxy of one through four carbons, alkylthio of one through four carbons, trifluoromethyl and trifluoromethoxy.

8. The method comprising administering to a warm-blooded animal, within an hour of each other, a compound selected from the group consisting of a 2-anilino-2-oxazoline and pharmaceutically acceptable acid addition salts of said oxazoline and, for each one part by weight of said compound, from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said oxazoline having the formula R 0-d-R where R, R, R and R are each selected from the group con sisting of hydrogen and alkyl of one through four carbons with the total number of carbons in each of these four substituents being eight; A is selected from the group consisting of hydrogen, alkyl of one through four carbons, alkoxy of one through four carbons and halogen; B is selected from the group consisting of alkyl of one through four carbons, alkoxy of one through four carbons and halogen; and C is selected from the group consisting of hydrogen, alkyl of one through four carbons, alkoxy of one through four carbons, halogen, alkyl-thio of one through four carbons, alkoxyalkyl wherein the alkoxy portion has one through two carbons and the alkyl portion has one through two carbons, alkylamino of one through two carbons, dialkylamino where each alkyl group has one through two carbons, trifluoromethyl and trifluoromethoxy. V

9. The method according to claim 1 wherein said anticholinergic agent is atropine sulfate and said oxazoline is 2- (5,6,7,8tetrahydrol -naphthylamino)-2-oxazoline.

10. The method according to claim I wherein said anticholinergic agent is atropine sulfate and said oxazoline is 2- (2,3-dimethylanilino)-2-oxazoline.

IL The method according to claim I wherein said anticholinergic agent is scopolamine hydrobromide and said oxazolinc is 2-(5,6,7,8-tctrahydro-l-naphthylamino)-2-oxazoline.

127 The method according to claim 1 wherein said anticholinergic agent is scopolamine hydrobromide and said oxazoline is 2-( 2,3-dimethylanilino)-2-oxazoline.

13. The method according to claim 1 wherein said anticholinergic agent is benzilic acid, phenyl cyclopentylglycolic acid, N-ethylpiperidinol ester, and said oxazoline is 2-(5,6,7,8- tetrahydro-l-naphthylamino)-2-oxazoline.

14. The method according to claim 1 wherein said anticholinergic agent is benzilic acid, phenyl cyclopentylglycolic acid, N-ethylpiperidinol ester, and said oxazoline is 2-(2,3 dimethylanilino)-2-oxazoline.

15. The method according to claim 1 wherein said anticholinergic agent is benzilic acid, beta-diethylaminoethyl ester, and said oxazoline is 2-(5,6,7,8-tetrahydro-lnaphthylamino)-2-oxazoline.

16. The method according to claim 1 wherein said anticholinergic agent is benzilic acid, beta-diethylaminoethyl ester, and said oxazoline is 2-(2,3-dimethyl-anilino)2-oxazoline.

17. A composition comprising one part by weight of an arylaminooxazoline and from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said arylaminoox azoline being selected from the group consisting of those of the following formulas and pharmaceutically acceptable acid addition salts thereof:

R O-dI-R where in each of Formulas l through (6) R, R, R and R are each separately selected from the group consisting of hydrogen and alkyl of one through four carbons with the total number of carbons in these four substituents being eight; where in each of Formulas (1) through 1 through 3 hydrogen atoms of the moiety selected from the group consisting of naphthyl, partially reduced naphthyl and indanyl can be replaced with a member selected from the group consisting of halogen, alkyl of one through four carbons, alkoxy of one through four carbons, alkylthio of one through four carbons, trifluoromethyl and trifluoromethoxy; and where in Formula (6) A is selected from the group consisting of hydrogen, alkyl of one through four carbons, alkoxy of one through four carbons and halogen;

B is selected from the group consisting of alkyl of one through four carbons, alkoxy of one through four carbons and halogen; and

C is selected from the group consisting of hydrogen, alkyl of one through four carbons, alkoxy ofone through four carbons halogen, alkylthio of one through four carbons. alkoxyalkyl wherein the alkoxy portion has one through two carbons and the alkyl portion has one through two carbons, alkylamino of one through two carbons, dialkylamino where each alkyl group has one through two carbons, trifluoromethyl and trifluoromethoxy.

18. A composition according to claim 17 wherein said centrally acting anticholinergic is a glycolate.

19. A composition comprising one part by weight of an arylaminooxazoline and from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said arylaminooxazoline being selected from the group consisting of those of the following formula and pharmaceutically acceptable acid addition salts thereof:

it where R, R, R and R are each selected from the group consisting of hydrogen and alkyl of one through four carbons with the total number of carbons in each of these four substituents being eight; and where one through three of the hydrogen atoms in the naphthyl group can be replaced with a member selected from the group consisting of halogen, alkyl of one through four carbons, alkoxy of one through four carbons, alkylthio of one through four carbons, trifluoromethyl and trifiuoromethoxy.

20. A composition comprising one part by weight of an arylaminooxazoline and from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said arylaminooxazoline being selected from the group consisting of those of the following formula and pharmaceutically acceptable acid addition salts thereof:

R Q was where R, R, R and R are each selected from the group consisting of hydrogen and alkyl of one through four carbons with the total number of carbons in each of these four substituents being eight; and where one through three of the hydrogen atoms in the partially reduced naphthyl group can be replaced with a member selected from the group consisting of halogen, alkyl of one through four carbons, alkoxy of one through four carbons, alkylthio of one through four carbons, trifluoromethyl and trifluoromethoxy.

21. A composition comprisinG one part by weight of an arylaminooxazoline and from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said arylaminooxazoline being selected from the group consisting of those of the following formula and pharmaceutically acceptable acid addition salts thereof:

where R, R, R and R are each selected from the group consisting of hydrogen and alkyl of one through four carbons with the total number of carbons in each of these four substituents being eight; and where one through three of the hydrogen atoms in the indanyl group can be replaced with a member selected from the group consisting of halogen, alkyl of one through four carbons, alkoxy of one through four carbons, alkylthio of one through four carbons, trifluoromethyl and trifluoromethoxy.

22. A composition comprising one part by weight of an arylaminooxazoline and from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said arylaminooxazoline being selected from the group consisting of those of the following formula and pharmaceutically acceptable acid addition salts thereof:

where R, R, R and R are each selected from the group consisting of hydrogen and alkyl of one through four carbons with the total number of carbons in each of these four substituents being eight; and where one through three of the hydrogen atoms in the partially reduced naphthyl group can be replaced consisting of halogen, alkyl of one through four carbons, alkoxy of one through four carbons, alkylthio of one through four carbons, trifluoromethyl and trifluoromethoxy.

23. A composition comprising one part by weight of an arylaminooxazoline and from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said arylaminooxazoline being selected from the group consisting of those of the following formula and pharmaceutically acceptable acid addition salts thereof:

where R, R, R", and R are each selected from the group consisting of hydrogen and alkyl of one through four carbons with the total number of carbons in each of these four substituents being eight; and where one through three of the hydrogen atoms in the indanyl group can be replaced with a member selected from the group consisting of halogen, alkyl of one through four carbons, alkoxy of one through four carbons, alkylthio of one through four carbons, trifluoromethyl and trifluoromethoxy.

24. A composition comprising one part by weight of an arylarninooxazoline and from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said arylaminooxazoline being selected from the group consisting of those of the following formula and pharmaceutically acceptable acid addition salts thereof:

where R, R, R and R are each selected from the group consisting of hydrogen and alkyl of one through four carbons with the total number of carbons in each of these four substituents being eight; A is selected from the group consisting of hydrogen, alkyl of one through four carbons, alkoxy of one through four carbons and halogen; B is selected from the group consisting of alkyl of one through four carbons, alkoxy of one through four carbons and halogen; and C is selected from the group consisting of hydrogen, alkyl of one through four carbons, alkoxy of one through four carbons, halogen, alkylthio of one through four carbons, alkoxyalkyl wherein the alkoxy portion has one through two carbons and the alkyl portion has one through two carbons, alkylamino of one through two carbons, dialkylamino where each alkyl group has one through two carbons, trifluoromethyl and trifluoromethoxy.

25. A composition comprising by weight 1 part of 2- (5,6,7,8-tetrahydro-l-naphthylamino)-2-oxazoline and 0.5-30 parts of atropine sulfate.

26. A composition comprising by weight 1 part of 2-(2,3- dimethylanilino)-2-oxazoline and 0.5-3O parts of atropine sulfate.

27. A composition comprising by weight 1 part of 2- (5,6,7,8-tetrahydro-l-naphthylamino)-2oxazoline and 0.5 to 30 parts of scopolamine hydrobromide.

28. A composition comprising by weight 1 part of 2-(2,3- dimethylanilino)-2-oxazoline and 0.530 parts of scopolamine hydrobromide.

29. A composition comprising by weight 1 part of 2- (5,6,7,8-tetrahydro-l-naphthylamino)-2-oxazoline and 0.5 to 30 parts of benzilic acid, phenyl cyclopentylglycolic acid, N-

ethylpiperidinol ester.

30. A composition comprising by weight l part of 2-(2,3- dimethylanilino)-2-oxazoline and 0.5 to 30 parts of benzilic acid, phenyl cyclopentylglycolic acid, N-ethylpiperidinol ester. 1

31. A composition comprising by weight 1 part of 2-(2,3- dimethylanilino)-2-oxazoline 0.5 to 30 parts of benzilic acid, phenyl cyclopentylglycolic acid, N-ethylpiperidinol ester.

31. A composition comprising by weight 1 part of 2- (5,6,7,8-tetrahydro-l-naphthylamino)-2-oxazoline and 0.5 to 30 parts of benzilic acid, beta-diethylaminoethyl ester.

32. A composition comprising by weight 1 part of 2-(2,3- dimethylanilino)-2-oxazoline and 0.5-30 parts of benzilic acid, beta-diethylaminoethylester. 

1. The method comprising administering to a warm-blooded animal two essential substances within 3 hours of each other, the first essential substance being a centrally acting anticholinergic agent and the second essential substance being selected from the group consisting of a 2-arylamino-2-oxazoline and pharmaceutically acceptable acid addition salts thereof, there being used from about 0.5 to 30 parts by weight of said anticholinergic agent for each part by weight of said second essential substance, and said 2-arylamino-2-oxazoline being a compound selected from the group consisting of
 2. The method according to claim 1 where said centrally acting anticholinergic is a glycolate.
 3. The method comprising administering to a warm-blooded animal, within an hour of each other, a compound selected from the group consisting of 2-(1 -naphthylamino)-2-oxazoline and pharmaceutically acceptable acid addition salts of said oxazoline and, for each one part by weight of said compound, from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said oxazoline having the formula
 4. The method comprising administering to a warm-blooded animal, within a hour of each other, a compound selected from the group consisting of a 2-(1,2,3,4-tetrahydro-1-naphthylamino)-2-oxazoline and pharmaceutically acceptable acid addition salts of said oxazoline and, for each one part by weight of said compound, from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said oxazoline having the formula
 5. The method comprising administering to a warm-blooded animal, within an hour of each other, a compound selected from the group consisting of a 2-(1-indanyl)-2-oxazoline and pharmaceutically acceptable acid addition salts of said oxazoline and, for each one part by weight of said compound, from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said oxazoline having the formula
 6. The method comprising administering to a warm-blooded animal, within an hour of each other, a compound selected from the group consisting of a 2-(5,6,7,8-tetrahydro-1-naphthylamino)-2-oxazoline and pharmaceutically acceptable acid addition salts of said oxazoline and, for each one part by weight of said compound, from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said oxazoline having the formula:
 7. The method comprising administering to a warm-blooded animal, within an hour of each other, a compound selected from the group consisting of a 2-(4-indanylamino)-2-oxazoline and pharmaceutically acceptable acid addition salts of said oxazoline and, for each one part by weight of said compound, from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said oxazoline having the formula
 8. The method comprising administering to a warm-blooded animal, within an hour of each other, a compound selected from the group consisting of a 2-anilino-2-oxazoline and pharmaceutically acceptable acid addition salts of said oxazoline and, for each one part by weight of said compound, from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said oxazoline having the formula
 9. The method according to claim 1 wherein said anticholinergic agent is atropine sulfate and said oxazoline is 2-(5,6,7,8-tetrahydro-1-naphthylamino)-2-oxazoline.
 10. The method according to claim 1 wherein said anticholinergic agent is atropine sulfate and said oxazoline is 2-(2,3-dimethylanilino)-2-oxazoline.
 11. The method according to claim 1 wherein said anticholinergic agent is scopolamine hydrobromide and said oxazoline is 2-(5,6,7, 8-tetrahydro-1-naphthylamino)-2-oxazOline.
 12. The method according to claim 1 wherein said anticholinergic agent is scopolamine hydrobromide and said oxazoline is 2-(2,3-dimethylanilino)-2-oxazoline.
 13. The method according to claim 1 wherein said anticholinergic agent is benzilic acid, phenyl cyclopentylglycolic acid, N-ethylpiperidinol ester, and said oxazoline is 2-(5,6,7,8-tetrahydro-1-naphthylamino)-2-oxazoline.
 14. The method according to claim 1 wherein said anticholinergic agent is benzilic acid, phenyl cyclopentylglycolic acid, N-ethylpiperidinol ester, and said oxazoline is 2-(2,3-dimethylanilino)-2-oxazoline.
 15. The method according to claim 1 wherein said anticholinergic agent is benzilic acid, beta-diethylaminoethyl ester, and said oxazoline is 2-(5,6,7,8-tetrahydro-1-naphthylamino)-2-oxazoline.
 16. The method according to claim 1 wherein said anticholinergic agent is benzilic acid, beta-diethylaminoethyl ester, and said oxazoline is 2-(2,3-dimethyl-anilino)-2-oxazoline.
 17. A COMPOSITION COMPRISING ONE PART BY WEIGHT OF AN ARYLAMINOOXAZOLINE AND FROM ABOUT 0.5 TO 30 PARTS BY WEIGHT OF A CENTRALLY ACTING ANTICHOLINERGIC AGENT, SAID ARYLAMINOOXAZOLINE BEING SELECTED FROM THE GROUP CONSISTING OF THOSE OF THE FOLLOWING FORMULAS AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF:
 18. A composition according to claim 17 wherein said centrally acting anticholinergic is a glycolate.
 19. A composition comprising one part by weight of an arylaminooxazoline and from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said arylaminooxazoline being selected from the group consisting of those of the following formula and pharmaceutically acceptable acid addition salts thereof:
 20. A composition comprising one part by weight of an arylaminooxazoline and from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said arylamiNooxazoline being selected from the group consisting of those of the following formula and pharmaceutically acceptable acid addition salts thereof:
 21. A composition comprisinG one part by weight of an arylaminooxazoline and from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said arylaminooxazoline being selected from the group consisting of those of the following formula and pharmaceutically acceptable acid addition salts thereof:
 22. A composition comprising one part by weight of an arylaminooxazoline and from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said arylaminooxazoline being selected from the group consisting of those of the following formula and pharmaceutically acceptable acid addition salts thereof:
 23. A composition comprising one part by weight of an arylaminooxazoline and from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said arylaminooxazoline being selected from the group consisting of those of the following formula and pharmaceutically acceptable acid addition salts thereof:
 24. A composition comprising one part by weight of an arylaminooxazoline and from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said arylaminooxazoline being selected from the group consisting of those of the following formula and pharmaceutically acceptable acid addition salts thereof:
 25. A composition comprising by weight 1 part of 2-(5,6,7,8-tetrahydro-1-naphthylamino)-2-oxazoline and 0.5-30 parts of atropine sulfate.
 26. A composition comprising by weight 1 part of 2-(2,3-dimethylanilino)-2-oxazoline and 0.5-30 parts of atropine sulfate.
 27. A composition comprising by weight 1 part of 2-(5,6,7,8-tetrahydro-1-naphthylamino)-2-oxazoline and 0.5 to 30 parts of scopolamine hydrobromide.
 28. A composition comprising by weight 1 part of 2-(2,3-dimethylanilino)-2-oxazoline and 0.5-30 parts of scopolamine hydrobromide.
 29. A composition comprising by weight 1 part of 2-(5,6,7,8-tetrahydro-1-naphthylamino)-2-oxazoline and 0.5 to 30 parts of benzilic acid, phenyl cyclopentylglycolic acid, N-ethylpiperidinol ester.
 30. A composition comprising by weight 1 part of 2-(2,3-dimethylanilino)-2-oxazoline and 0.5 to 30 parts of benzilic acid, phenyl cyclopentylglycolic acid, N-ethylpiperidinol ester.
 31. A composition comprising by weight 1 part of 2-(2,3-dimethylanilino)-2-oxazoline 0.5 to 30 parts of benzilic acid, phenyl cyclopentylglycolic acid, N-ethylpiperidinol ester.
 31. A composition comprising by weight 1 part of 2-(5,6,7,8-tetrahydro-1-naphthylamino)-2-oxazoline and 0.5 to 30 parts of benzilic acid, beta-diethylaminoethyl ester.
 32. A composition comprising by weight 1 part of 2-(2,3-dimethylanilino)-2-oxazoline and 0.5-30 parts of benzilic acid, beta-diethylaminoethyl ester. 